Continuous Glycoprotein-130-Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction
Continuous Glycoprotein-130-Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction
复制标题
DOI：
10.1161/circulationaha.109.933127
复制
发表时间：
2010-07-13
期刊：
影响因子：
37.8
通讯作者：
Drexler, Helmut
中科院分区：
文献类型：
--
作者：
Hilfiker-Kleiner, Denise;Shukla, Praphulla;Drexler, Helmut
背景--在心肌梗塞患者中，血清中高水平的白介素6细胞因子预示着不良的预后。白介素6细胞因子的共同受体-糖蛋白130(Gp130)，通过Janus激酶/信号转导和转录激活因子(STAT)、细胞质蛋白酪氨酸磷酸酶/细胞外信号调节激酶和磷酸肌醇-3-激酶/Akt通路传递信号，这些通路的调节至少部分依赖于gp130酪氨酸-757残基。通过对心肌细胞特异性gp130(Y757F)突变小鼠的分析，我们探讨了心肌梗死后gp130信号转导紊乱的影响。方法和结果：利用心肌细胞限制性α-肌球蛋白重链-Cre-重组酶-loxP系统，获得了gp130(Y757F)突变心肌细胞(α-MHC-Cre(Tg/-)；gp130(fl/Y757F)[Y757F])，所有其他细胞都携带至少1个功能gp130基因，确保gp130信号正常。Y757F小鼠在3月龄时表现出正常的心功能和形态，与它们的非突变小鼠相当。在对心肌梗死的反应中，Y757F小鼠表现出更高的死亡率，与左心室破裂发生率增加、持续性心脏炎症和心力衰竭有关。这些不良反应与延长和增强STAT3的激活以及IL-6和补体激活的甘露糖结合凝集素C的表达增加有关。眼镜蛇蛇毒因子抑制补体系统的药理作用减轻了炎症，防止了左室破裂，并改善了Y757F小鼠的心功能。在Y757F小鼠中，STAT3基因下调(STAT3(FLOX/+))仅限于心肌细胞，可防止白细胞介素6的广泛上调、补体激活和持续炎症，并降低亚急性心肌梗死的左室破裂发生率、心力衰竭和死亡率。结论亚急性心肌梗死时gp130介导的STAT3激活下调可能促进心脏炎症、不良重构和心力衰竭，提示高水平的白介素6可能是心肌梗死后的致病机制。(发行量。2010年；122：145-155。)
Background-In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction.Methods and Results-The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alpha MHC-Cre(tg/-); gp130(fl/Y757F) [Y757F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y757F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y757F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y757F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y757F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction.Conclusion-Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction. (Circulation. 2010; 122: 145-155.)